Medical device having surface modification with superoxide dismutase mimic

ABSTRACT

A medical device comprising a substrate having a plasma polymerized functionality bonded to at least a portion of the substrate. A superoxide dismutase mimic agent having a complimentary functional group to the plasma polymerized functionality is bonded to the portion of the substrate by bonding to the plasma polymerized functionality.

RELATED APPLICATION

This application is a continuation in part of U.S. patent applicationSer. No. 09/827,887 filed on Apr. 6, 2001 by Charles Claude and JeongLee, which is entitled “Medical Device Chemically Modified By PlasmaPolymerization.”

BACKGROUND OF THE INVENTION

This invention relates to implantable medical devices for therapeutic ordiagnostic uses such as endocardial cardiac pacemaker leads and/orcardioverter/defibrillator leads. There are various types of transvenouspacing and cardioversion or defibrillation leads developed forintroduction into different chambers of a patient's heart. Theseimplantable leads are usually constructed with an outer biocompatibleinsulating sheath encasing one or more conductors, one of which istypically attached at its distal end to an exposed tip electrode.

The tip electrode is usually placed in contact with endocardial tissueat the chosen site of the heart chamber by percutanaeous introductionand passage through a venous access, often the sub-clavian vein or oneof its tributaries, which leads to the heart chamber. As the lead isimplanted into the patient, one typical response to this implantation isthe fibrotic encapsulation (e.g., protein encapsulations) of the lead.The presence of fibrotic encapsulation can compromise the performance ofthe lead, especially in more permanent implantation situations.Furthermore, during the removal of the lead, it is typical to require asurgical procedure to remove a portion of the lead. For example, after aportion of a lead is excised from its position, a suspended weight(approximately 5 lbs) is attached to the exposed portion of the lead toallow for an application of a constant force over a period of severalhours to extract the lead from the fibrotic encapsulation. Such removalprocedure creates discomfort and pain to the patient.

It has been shown in the literature that modification of a plastic(e.g., polyethylene and polyetherurethane) with superoxide dismutasemimic (SODm) results in a significant reduction in fibroticencapsulation in an implanted foreign device. See “Modification ofInflammatory Response to Implanted Biomedical Materials In Vivo bySurface Bound Superoxide Dismutase Mimics” authored by Kishore Udipi,et. al, Journal of Biomedical Material Research 2000, Sep. 15,51(4):549-60. The method contemplated by Udipi does not result in a highdensity grafting of SODm on the surface of the plastic and is dependenton the composition of the substrate.

It would be a significant advantage to provide endocardial cardiacpacemaker leads and/or cardioverter/defibrillator leads or other medicaldevice component having SODm surface treatment with improved bondabilityand densities, on a variety of substrates including those difficult tomodify such as fluoropolymers.

SUMMARY OF THE INVENTION

A medical device coated with superoxide dismutase mimic (SODm) andmethods to fabricate the same are described. In one example, the medicaldevice comprises a substrate having a plasma polymerized functionalitybonded to at least a portion of the substrate. A superoxide dismutasemimic agent having a complimentary functional group to the plasmapolymerized functionality is bonded to the portion of the substrate bybonding to the plasma polymerized functionality.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated by way of example and notlimitation in the figures of the accompanying drawings, in which likereferences indicate similar elements and in which:

FIG. 1 illustrates an exemplary pacemaker lead of the present inventionthat can be coated with SODm;

FIG. 2 illustrates a cross-sectional view of the exemplary pacemakerlead of FIG. 1 shown to include a polymeric insulation layer and aconductive element;

FIG. 3 illustrates a cross-sectional view of the exemplary pacemakerlead of FIG. 1 shown to include a polymeric insulation layer and severalconductors;

FIG. 4 illustrate a cross-sectional view of the exemplary pacemaker leadof FIG. 1 shown to include a polymeric insulation layer which is treatedto include plasma polymerized functionality and coated with a SODmcoating;

FIG. 5 illustrates an exemplary method of coating a pacemaker lead withSODm;

FIG. 6 illustrates another exemplary method of coating a pacemaker leadwith SODm;

FIG. 7 illustrates yet another exemplary method of coating a pacemakerlead with SODm;

FIG. 8 illustrates further yet another exemplary method of coating apacemaker lead with SODm;

FIG. 9 illustrates another exemplary method of coating a pacemaker leadwith SODm; and

FIG. 10 illustrates an exemplary plasma chamber that can be used topractice the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In the following description, for purposes of explanation, numerousspecific details are set forth in order to provide a thoroughunderstanding of the present invention. It will be evident, however, toone skilled in the art that the present invention may be practicedwithout these specific details. In other instances, specific apparatusstructures and methods have not been described so as not to obscure thepresent invention. The following description and drawings areillustrative of the invention and are not to be construed as limitingthe invention.

The present invention is directed to coating implantable medical devicessuch as endocardial cardiac pacemaker leads and/orcardioverter/defibrillator leads. Exemplary embodiments of the presentinvention are applicable to the medical devices having components thatare designed for being implanted inside a patient's body. Thesecomponents are often made out of or coated with biocompatible materialssuch as polymeric materials selected from the group consisting of afluoropolymer, polytetrafluoroethylene, expandedpolytetrafluoroethylene, high density polyethylene, polyimide,polyetherether ketone, polyimide, polyolefin, polyurethane,polycarbonate urethane, siliconized urethane, and silicone rubber.Furthermore, the medical device of the present invention comprises anelectrically conductive electrophysiology lead that can be implanted inthe patient's heart. Alternatively, the medical device of the presentinvention comprises a pacemaker lead that can be implanted in thepatient's heart. And, the medical device of the present inventioncomprises an electrical generator and an electrically conductiveelectrophysiology lead that can be implanted in the patient's heart.

One example of such medical device is a pacemaker lead and/or acardioverter/defibrillator lead. A pacemaker lead and/or a cardioverterdefibrillator lead that the present invention can be applied to haselectrical signals generating circuitry for pacing and defibrillatingfunctions and that the lead conducts the signals to the appropriatetreatment sites in a patient's body. Such a pacemaker lead and/or acardioverter defibrillator lead is well know in the art. An exemplarypacemaker lead and/or a cardioverter defibrillator lead of the presentinvention has at least a portion being coated with a SODm coating havingfunctional groups such as amine binding sites or carboxylate bindingsites. The portion being coated with SODm is first treated such that itincludes a plasma polymerized functionality complimentary to thefunctional group on the SODm. The exemplary pacemaker lead is coatedwith a high density SODm layer.

FIG. 1 shows a side view of an exemplary pacemaker lead 100 that thepresent invention can be applied to. The lead 100 includes an elongatedlead body which is covered with an insulation sheath 102. The lead bodymay be coupled to a tip electrode 104 and a connector assembly 106having sealing rings 108 which engage connector element or pin 120. Tipelectrode 104 is the conductive point for the pacemaker lead and istypically not insulated with insulation sheath 102. Pin 120 may becoupled to an implantable pulse generator (not shown) at the proximalend of the lead body. The connector assembly 106 may be constructedusing techniques known in the art and may be fabricated of siliconerubber, polyurethane or other suitablepolymer. The connector pin 120 maybe fabricated of stainless steel or other conductive material.

FIG. 2 illustrates, in a cross-sectional view, that the pacemaker leadin this example also includes a conductive element 112 which isencapsulated by insulation sheath 102 and which is coupled to tipelectrode 104. FIG. 3 illustrates that in another embodiment, conductiveelement 112 may also includes several conductors, (e.g., conductor 114,115, and 116) each of which may be insulated by a silicone jacket 118.As illustrated, conductive element 112 is coated with insulation sheath102 which may be fabricated of silicone rubber, polyurethane,fluoropolymers, polytetrafluoroethylene (PTFE), expandedpolytetrafluoroethylene (ePTFE), polyelefins such as high densitypolyethylene (HDPE), and engineering thermoplastic, thermoset polymerssuch as polyetherether ketone (PEEK), polyimide, urethane, polyurethane,polycarbonate urethane, siliconized urethane, silicone rubber, or anyother suitable material. Insulation sheath 102 is generally referred toas polymeric insulation layer 102 throughout this document.

FIG. 4 illustrates a cross-sectional view of a section 101 of pacemakerlead 100 of the present invention. Section 101 is taken through aportion of the pacemaker lead that will be coated with SODm coatings 103of the present invention. In a preferred embodiment, section 101includes portions of pacemaker lead 100 that are implanted inside apatient's body. Section 101, however, does not show electrode tip 104since that portion is typically the conductive point of pacemaker leadand includes no polymeric insulation layer 102. The electrode tip 104 iselectrically conductive and not covered by insulation so that it makesproper electrical contact with the tissue of the patient's body.

In a preferred embodiment, it is to be noted that the electrode tip 104should remain free of coating to maintain unimpeded electricalconductivity. Thus, no SODm coating will be done to the electrode tip104.

FIG. 4 further illustrates that pacemaker lead 100 includes conductiveelement 112 and polymeric insulation layer 102 coated around theconductive element 112. In one example, polymeric insulation layer 102is a substrate upon which a plasma polymerized functionality layer 140is formed. As plasma polymerized functionality layer 140 is formedaround polymeric insulation layer 112 at least a portion of pacemakerlead 100 is coated with plasma polymerized functionality layer 140. Inone example, the entire length of polymeric insulation layer 102 ofpacemaker lead 100 is coated with plasma polymerized functionality layer140. Plasma polymerized functionality layer 140 facilitates the bondingof SODm coating 103 to the surface of the insulation layer with highdensities of the SODm molecules on the surface polymeric insulationlayer of the lead. In one exemplary embodiment, the SODm coating 103 hasa density within the range of 10 μg/cm² to 50 μg/cm². In anotherembodiment, the SODm coating 103 has a density of 30 μg/cm². Forcomparison purpose, conventional methods of coating SODm onto asubstrate yield an SODm layer having density in the range of 1 μg/cm² to10 μg/cm². The SODm coating 103 of the present invention thus has a muchhigher density as compared to convention methods of forming the SODmlayer.

In one example, plasma polymerized functionality layer 140 comprises offunctional groups such as carboxylic acid, amine or sulfate. SODmcoating 103 includes functionality groups such as amine or carboxylatewhich is complimentary to the plasma polymerized functionality layer 140to enhance the bonding of the plasma polymerized functionality layer tothe SODm coating 103. In one instance, plasma polymerized functionalitylayer 140 comprises of carboxylic acid groups and SODm coating 103comprises of amino groups. These two functionality groups are thuscomplimentary to each other. In another instance, both the plasmapolymerized functionality layer 140 and the SODm coating 103 compriseamine functional groups. A crosslinker is used to bond these two layerstogether (see FIG. 8).

In one example, only a portion of the lead is coated with plasmapolymerized functionality layer 140. The portion that is coated withplasma polymerized functionality layer 140 is the portion that will becoated with SODm coating 103. The remaining portions of plasmapolymerized functionality layer 140 of the pacemaker lead thus, may notneed to be treated with the plasma polymerized functionality layer 140and are left for other purposes (e.g., drug delivery) in the use of thepacemaker lead.

In one exemplary embodiment, the surfaces of pacemaker lead 100 ischemically modified by modifying polymeric insulation layer 102. Thechemically modified surfaces of pacemaker lead 100 comprise plasmapolymerized functionality layer 140 deposited on the surfaces ofpolymeric insulation layer 102 by plasma polymerization. In a presentlypreferred embodiment, polymeric insulation layer 102 is chemicallymodified to create a carboxylate-rich surface from a plasma statederived from an organic carboxylate decomposed in an radio frequencyfield, which will be denoted as an RF field within the embodiments.However, a variety of suitable functionalities can be plasma polymerizedon the surfaces of the pacemaker lead including amine, and sulfatefunctionalities. In a presently preferred embodiment, the plasmapolymerized carboxylate film comprises an acrylate or acrylate-likepolymer layer deposited onto the polymeric insulation layer by exposingthe polymeric insulation layer to a plasma, which in a presentlypreferred embodiment is an acrylic acid plasma. One of skill in the artwill recognize that some fragmentation of the acrylate typically occursduring plasma polymerization, resulting in an acrylate-like polymerlayer of fragmented acrylate. In a presently preferred embodiment, theacrylate is acrylic acid. While discussed below primarily in terms ofapplying a carboxylate film by plasma polymerization of acrylic acid onthe polymeric insulation layer, it should be understood that a varietyof functionalities (such as amines) on a variety of substrates may beused.

It will be appreciated that not all portions of a pacemaker lead 100needs to be chemically modified. The portions that need to be coatedwith SODm coating 103 are portions to undergo chemical modification. Inone exemplary method, the whole pacemaker lead 100 is placed in thereaction chamber for chemical modification. Masking is used to block offthe portions that do not need the chemical modification. For instance, amasking agent such as polyvinyl alcohol is coated over the portions(e.g., the distal end of the electrode tip 104 portion) that do not needthe chemical modification. This masking can be removed at the end of theprocess when SODm coating 103 is successfully coated on polymericinsulation layer 102 of pacemaker lead 100.

In a presently preferred embodiment, the polymeric insulation layer ischemically modified to create a carboxlylic acid rich surface byexposure to an acrylic acid plasma. In one embodiment, the methodcomprises introducing the polymeric insulation layer into an argonplasma field to remove organic processing debris from the surface of thepolymeric insulation layer before deposition of the plasma polymerizedfilm. The method can be carried out in a plasma reaction chamber 30illustrated in FIG. 10 (see below). Preferably, polymeric insulationlayer 102 is pre-treated in the argon plasma field at about 100 to 250mTorr, preferably about 150 mTorr, with an applied RF field of about 80to 250 W, preferably about 100 W, for about 1 to 10 minutes, preferablyabout 3 minutes. During the pretreatment, argon gas is introduced intothe chamber with a flow rate of approximately 230 sccm. After the threeminutes plasma pretreatment, the pressure in the plamsa chamber isreduced to less than 1 mTorr.

An acrylic acid plasma is then applied to the polymeric insulation layerto produce a carboxylate rich film on the polymeric insulation layer.The plasma power is formed by an application of a RF field between 20KHz and 2.45 GHz. In this embodiment the RF field has a frequency of13.56 MHz. The plasma power together with a flow of acrylic acid createsan acrylic acid plasma having power of about 80 to about 200 W, andpreferably about 100 W. The acrylic acid flow rate for the reactionranges from 0.1 to 0.5 ml/min, and preferably at 0.2 ml/min. The acrylicacid may be mixed with a carrier gas such as carbon dioxide introducinginto the chamber with a flow rate of approximately 90 sccm. The pressurefor the reaction is maintained at about 150 mTorr. The concentration ofthe carboxylate is dependent on the decomposition of the acrylic acid inthe RF field. The parameters which vary the decomposition of acrylicacid include the plasma power, wherein the carboxylate concentrationdecreases as the RF power increases. The acrylic acid plasma is appliedfor about 3 to 10 minutes, preferably about 5 to 10 minutes, dependingon the desired thickness of the carboxylate rich film. The thickness ofthe carboxylate rich film is about 25 to 150 nm, preferably about 50 toabout 125 nm. In one embodiment, following exposure to the acrylic acidplasma, the plasma field is purged with argon under no RF power to allowsurface free-radicals to recombine before exposure to atmosphericoxygen. For instance, after the reaction time, the RF power isterminated and the pressure in the plasma chamber is reduced to below 1mTorr. And, upon achieving the low pressure, the plasma chamber ispurged with argon gas having a flow rate of approximately 250 sccm whilemaintaining a pressure of about 230 mTorr with no RP power for 3minutes. After these 3 minutes, the plasma chamber was vented toatmospheric pressure.

In a presently preferred embodiment, carbon dioxide is included in theacrylic acid plasma to limit the rate of decarboxylation from thesurface of the polymeric insulation layer. The composition ofpolymerized material is dependent on the fragmentation of the acrylicacid. The fragmentation process results in reactive species thatpolymerize with the substrate surface and species that becomenonreactive gaseous products. One such nonreactive gaseous product is aresult of the decarboxylation of the acrylic acid with the formation ofcarbon dioxide.. Thus, by adding carbon dioxide to the acrylic acidplasma, the decarboxylation of the organic reactive species in the RFfield can be decreased. In a preferred embodiment, the carbon dioxideconcentration in the acrylic acid plasma is about 8% to about 10%,preferably about 9%.

The plasma polymerization results in a thin carboxylate film depositedonto the substrate (e.g., polymeric insulation layer 102 of pacemakerlead 100), and will be described as the plasma polymerized functionalitywithin the embodiments. The surface of the substrate has the samepolymer composition as the bulk of the substrate, so that the surfaceand the bulk of the substrate have similar carboxylate concentrationfollowing deposition of the plasma polymerized film. The similarcarboxylate concentration minimizes the time dependent variation of thesurface energy. The structural integrity of the polymeric insulationlayer of the lead is minimally or not effected by the plasmapolymerization.

In another example, the polymeric insulation layer is chemicallymodified to create an amine-rich surface by exposure to an allylamineplasma. The same method discussed above can be use. The plasma chamberis fed with allylamine having a flow rate of 0.225 ml/min. A CO₂ carriergas is not required in this example. The plasma power is formed with anRF source of 13.56 MEZ as above. The power is supplied at 30 watts andthe pressure is maintained at approximately 100 mTorr. All otherconditions can be the same as for the creating of the carboxylic acidrich surface discussed above.

The methods to create the plasma polymerized functionality on thepacemaker lead 100 above can be applied to a variety of medical devicesmade out of a variety of materials. The parameters above may be adjustedto suit different types of materials. For instance, when HDPE, or PTFEis used the power used in the pretreatment step may be lowered to 80-100watts.

FIG. 5 illustrates an exemplary method 500 to coat SODm on the surfacesof polymeric insulation layer 102 of pacemaker lead 100 of the presentinvention. As set forth in steps 502, 504, 506, and 508, pacemaker lead100 is treated so that it comprises a plasma polymerized functionalityincluding carboxylic functional groups on the surface of polymericinsulation layer 102 of pacemaker lead 100. Steps 502, 504, 506 and 508are illustrations of the plasma polymerization methods described above.As set forth in step 510, the pacemaker lead 100 comprising plasmapolymerized functionality is then placed in a reaction tube (e.g., aglass tube) that allows full-linear covering of the carboxylatedpacemaker lead 100 without a 180-degree bend. The carboxylated pacemakerlead 100 is allowed to react with an SODm-EDC solution 516, and in oneexample, for 4 hours with agitating or shaking at room temperature.

As mentioned, SODm stands for superoxide dismutase mimics, which are lowmolecular weight molecules that catalyze the conversion of superoxideinto oxygen and hydrogen peroxide. In one example, the SODm has amolecular weight ranging from 500 to 600 Da. Examples of SODm includethe macrocyclic ligands taught by Riley et al. in U.S. Pat. No.6,084,093 and U.S. Pat. No. 5,610,293. These patents are herebyincorporated by reference. The SODm including the macrocyclic ligandsare related to manganese (II) or manganese (III) complexes ofnitrogen-containing fifteen-membered marcocyclic ligands. Alternatively,the SODm can be obtained from chemical suppliers such as MetaphorePharmaceuticals Inc., (1910 Innerbelt Business Center Drive St. Louis,Mo. 63114)For example, an SODm from Metaphore Pharmaceuticals Inc. has aproduct code of M-40470 SODm which has the generic chemical name of[Manganese(II)dichloro{24-[2-aminoehtylthio-](4R,9R14R,19R)-3,10,13,20,26-pentaazatetracyclo[20.3.1.0^(4,9).0^(14,19)]hexacosa-1(26),22(23),24-trienewith the formula C₂₃H₄₀N₆Cl₂SMn. Any variation of the formula above astaught by the Riley patents and any variation of the SODm from MetaphorePharmaceuticals Inc. can also be used in accordance with the presentinvention, provided some functional ligand is available on the moleculefor coupling to a surface containing a functional reactive group.Examples of functional reactive groups on a surface for coupling areprimary amine, carboxyl, or sulfate. It is to be understood that theabove examples are not to be interpreted as limiting.

EDC stands for 1-Ethyl-3-(3-Dimethylaminopropyl) carbodiimideHydrochloride) which can be obtained from Pierce, Rockford, Ill. In oneexample, the SODm solution shown at step 514 is prepared by mixing SODm(e.g., Metaphor M40470 SODm) having a primary amine ligand in a buffersuch as MES/KOH (pH 6-6.5). The SODm solution 514 has a concentrationbetween 0.1 mg/mL to 1.0 mg/mL. The SODm-EDC solution 516 is thencreated by dissolving EDC from step 512 into SODm solution 514 at 4-12mg of EDC per 1 mL of SODm solution.

The reaction yields a 0-length amide linkage between the carboxylsurface (the plasma polymerized functionality) on polymerized insulationlayer 102 and the SODm amine creating a covalent bonding between thepolymeric insulation layer 102 of pacemaker lead 100 and the SODm. Thefinal product is pacemaker lead 100 comprising insulation layer 102 thatfurther comprises plasma polymerized functionality which is covalentlybonded to a SODm having amine functional groups via amide linkages asillustrated in box 518. The SODm bonded to the pacemaker lead 100retains the function of converting superoxide into oxygen and hydrogenperoxide. The presence of the SODm on the pacemaker lead 100 thussignificantly reduces fibrotic encapsulation on the pacemaker lead 100.

FIG. 6 illustrates another exemplary method 600 to coat SODm on thesurfaces of polymeric insulation layer 102 of pacemaker lead 100 of thepresent invention. As set forth in steps 602, 604, 606, and 608,pacemaker lead 100 is treated so that it comprises a plasma polymerizedfunctionality including carboxylic functional groups on the surface ofpolymeric insulation layer 102 of pacemaker lead 100. Steps 602, 604,606 and 608 are illustrations of the plasma polymerization methoddescribed above. As set forth in step 610, pacemaker lead 100 comprisingplasma polymerized functionality is then placed in a reaction tube(e.g., a glass tube) that allows full-linear covering of thecarboxylated pacemaker lead 100 without a 180-degree bend. The plasmapolymerized functionality on pacemaker lead 100 is allowed to react withan SODm-EDC solution 616, and in one example, for 4 hours with agitatingor shaking at room temperature.

In one example, the SODm solution shown at step 614 is prepared bymixing SODm (e.g., Metaphor M40470 SODm) having a primary amine ligandin a buffer such as MES/KOH (pH 6-6.5). The SODm 614 solution has aconcentration between 0.1 mg/mL to 1.0 mg/mL. The SODm solution at step614 may further include an amine terminated agent such as amineterminated polyethylene glycol (e.g., PEG, from Shearwater 2V3F0F01).The PEG concentration in the SODm solution ranges form 0.1 mg/mL to 5mg/mL. The SODm-PEG-EDC solution 616 is then created by dissolving EDCfrom step 612 into SODm solution 614 at a concentration between 4-12 mgof EDC per 1 mL of SODm solution.

The reaction yields a 0-length amide linkage between the carboxylsurface (the plasma polymerized functionality) on polymerized insulationlayer 102 and the SODm amine creating a covalent bonding between thepolymeric insulation layer 102 of pacemaker lead 100 and the SODm. Thefinal product is pacemaker lead 100 comprising insulation layer 102 thatfurther comprises plasma polymerized functionality which is covalentlybonded to a SODm via having amine functional groups amide linkages asillustrated in box 618. The SODm bonded to the pacemaker lead 100retains the function of converting superoxide into oxygen and hydrogenperoxide. The presence of the SODm on the pacemaker lead 100 thussignificantly reduces fibrotic encapsulation on the pacemaker lead 100.

FIG. 7 illustrates yet, another exemplary method 700 to coat SODm on thesurfaces of polymeric insulation layer 102 of pacemaker lead 100 of thepresent invention. As set forth in steps 702, 704, 706, and 708,pacemaker lead 100 is treated so that it comprises a plasma polymerizedfunctionality including carboxylic functional groups on the surface ofpolymeric insulation layer 102 of pacemaker lead 100. Steps 702, 704,706 and 708 are illustrations of the plasma polymerization methoddescribed above.

In this exemplary method, pacemaker lead 100 comprising plasmapolymerized functionality is further treated such that the carboxylatefunctional group on insulation layer 102 is further derivatized with anacid chloride such as thionyl chloride. In one example, step 710 setsforth that pacemaker lead 100 comprising plasma polymerizedfunctionality is dipped in a dipolar aprotic or anhydrous solvent suchas N,N-Dimethyl acetamide (DMAC), dimethyl sulfoxide (DMSO), or acetonewhich includes thionyl chloride at 1% to 10% (w/v) for 30 to 60 minutes.The pacemaker lead 100 is then removed and rinsed with DMAC, DMSO,acetone, or methylene chloride. The pacemaker lead 100 comprising plasmapolymerized functionality now includes derivatives that are acidchlorides.

As set forth in step 711, pacemaker lead 100 comprising plasmapolymerized functionality and acid chloride derivatives is then placedin a reaction tube (e.g., a glass tube) that allows full-linear coveringof the carboxylated pacemaker lead 100 without a 180-degree bend. Thepacemaker lead is allowed to react with SODm-PEG-EDC solution 716 for 30to 60 minutes at room temperature with agitating or shaking.

SODm-PEG-EDC solution 716 is made by mixing EDC and SODm andpolyethylene glycol (PEG) together. In one example, the SODm solutionshown at step 714 is prepared by mixing SODm (e.g., Metaphor M40470SODm) having a primary amine ligand in a buffer such as MES/KOH (pH6-6.5). The SODm solution has a concentration between 0.1 mg/mL to 1.0mg/mL. The SODm solution at step 674 further includes PEG which is anamine terminated agent that can be obtained from Shearwater (catalog#2V3F0F01). The PEG concentration in the SODm solution ranges from 0.1mg/mL to 5 mg/mL. The SODm-PEG-EDC solution 716 is then finally createdby dissolving EDC from step 712 into SODm solution 714 at aconcentration between 4-12 mg of EDC per 1 mL of SODm solution.

Alternatively, PEG is not added to the SODm solution 714, this SODmsolution is thus similar to solution 514 described in FIG. 5. TheSODm-EDC solution 716 is also made similar to the SODm-EDC solution 516above.

The reaction yields a 0-length amide linkage between the carboxylsurface (the plasma polymerized functionality) on polymerized insulationlayer 102 and the SODm amine creating a covalent bonding between thepolymeric insulation layer 102 of pacemaker lead 100 and the SODm. Thefinal product is pacemaker lead 100 comprising polymeric insulationlayer 102 that further comprises plasma polymerized functionalityderivatives which is covalently bonded to SODm having amine functionalgroups via amide linkages as illustrated in box 718. The SODm bonded tothe pacemaker lead 100 retains the function of converting superoxideinto oxygen and hydrogen peroxide. The presence of the SODm on thepacemaker lead 100 thus significantly reduces fibrotic encapsulation onthe pacemaker lead 100.

FIG. 8 illustrates another exemplary method 800 to coat SODm on thesurfaces of polymeric insulation layer 102 of pacemaker lead 100 of thepresent invention. As set forth in steps 802, 804, 806, and 808,pacemaker lead 100 is treated so that it comprises a plasma polymerizedfunctionality including amine functional groups on the surface ofpolymeric insulation layer 102 of pacemaker lead 100. Steps 802, 804,806 and 808 are illustrations of the plasma polymerization methoddescribed above. As set forth in step 810, pacemaker lead 100 comprisingplasma polymerized amine functionality is then placed in a reaction tube(e.g., a glass tube) that allows full-linear covering of the aminatedpacemaker lead 100 without a 180-degree bend. The plasma polymerizedamine functionality on pacemaker lead 100 is allowed to react with aSODm solution 816 having a crosslinker. In one example, agitating orshaking at room temperature for 30 to 60 minutes is required.

In one example, the SODm solution 816 having the crosslinker is preparedas followed. First, the SODm solution shown at step 814 is prepared bymixing SODm (e.g., Metaphor M40470 SODm) having a primary amine ligandin a buffer such as MES/KOH (pH 5.5-6). The SODm solution 814 has aconcentration between 0.1 mg/mL to 1.0 mg/mL. In another example, theMED/KOH buffer is replaced with bicarbonate buffer at pH 7.0. Then, theSODm solution 816 having the crosslinker is created by mixing a watersoluble crosslinker such as homobifunctional N-hydroxysuccinimide ester(di-NHS ester) from step 812 into SODm solution 814 at a concentrationbetween 1-15 mg di-NHS ester per 1 mL of SODm solution 814. An exemplarydi-NHS ester crosslinker includes disulfosuccinimidyl suberate,dissuccinimidyl suberate, and bis(sulfosuccinimidyl)suberate made byPierce.

The reaction yields 2 amide linkages between the amine functional groups(the plasma polymerized functionality) on polymerized insulation layer102 and the SODm amine creating a covalent bonding between the polymericinsulation layer 102 of pacemaker lead 100 and the SODm. The finalproduct is pacemaker lead 100 comprising insulation layer 102 thatfurther comprises plasma polymerized functionality which is covalentlybonded to SODm having amine functionality via amide linkages asillustrated in box 818. The SODm bonded to the pacemaker lead 100retains the function of converting superoxide into oxygen and hydrogenperoxide. The presence of the SODm on the pacemaker lead 100 thussignificantly reduces fibrotic encapsulation on the pacemaker lead 100.

FIG. 9 illustrates another exemplary method 900 to coat SODm on thesurfaces of polymeric insulation layer 102 of pacemaker lead 100 of thepresent invention. This method is similar to method 800 described above.As set forth in steps 902, 904, 906, and 908, pacemaker lead 100 istreated so that it comprises a plasma polymerized functionalityincluding amine functional groups on the surface of polymeric insulationlayer 102 of pacemaker lead 100. Steps 902, 904, 906 and 908 areillustrations of the plasma polymerization method described above. Asset forth in step 910, pacemaker lead 100 comprising plasma polymerizedamine functionality is then placed in a reaction tube (e.g.,.a glasstube) that allows full-linear covering of the aminated pacemaker lead100 without a 180-degree bend. The plasma polymerized aminefunctionality on pacemaker lead 100 is allowed to react with an SODmsolution 916 having a crosslinker. In one example, agitating or shakingat room temperature for 30 to 60 minutes is required.

In one example, the SODm solution 916 having the crosslinker is preparedas followed. First, the SODm solution shown at step 914 is prepared bymixing SODm (e.g., Metaphor M40470 SODm) having a primary amine ligandin a high pH buffer such as sodium carbonate/HCl buffer at pH 7.5 to 9.0and 0.1 mM. The concentration of SODm in the buffer is approximately 0.1to 1 mg/mL. Then, the SODm solution 916 having the crosslinker iscreated by dissolving a bis imidoester crosslinker from step 912 intoSODm solution 914 at a concentration between 1 to 10 mg of bisimidoester crosslinker per 1 mL of SODm solution 914. An exemplary bisimidoester crosslinkers include dimethyl pimelimidate, dimethylsuberimidate, dimethyl adipimidate, and dimethyl3.3-dithiobispropionimidate made by Pierce.

The reaction yields 2 imidoamide linkages with a C4 spacer (fordimethyladipimidate) between the amine surface (the plasma polymerizedfunctionality) on the plasma polymerized insulation layer 102 and theSODm amine creating covalent bonding between the polymeric insulationlayer 102 of pacemaker lead 100 and the SODm. The final product ispacemaker lead 100 comprising insulation layer 102 that furthercomprises plasma polymerized functionality which is covalently bonded toSODm having amine functional groups via amide linkages as illustrated inbox 918. The SODm bonded to the pacemaker lead 100 retains the functionof converting superoxide into oxygen and hydrogen peroxide. The presenceof the SODm on the pacemaker lead 100 thus significantly reducesfibrotic encapsulation on the pacemaker lead 100.

The above-described methods can be performed by any suitable apparatusknown to one of ordinary skill in the art. One example of such anapparatus is a plasma reaction chamber 30 illustrated in FIG. 10.Chamber 30 can be cylindrical in shape and can be fabricated from anynumber of suitable materials, such as glass and aluminum. By way ofexample, chamber 30 can be from about 4 inches (10.16 cm) to about 15inches (38.1 cm) in diameter and from about 5 inches (12.7 cm) to about18 inches (45.72 cm) in height.

A mandrel 32 holds a single medical device 34 (e.g., pacemaker lead 100)or multiple medical devices 34 in position relative to the interior wallof chamber 30. Medical device 34 can be oriented at any position withinchamber 30 as required to achieve a desired implantations or deposition.One end of mandrel 32 can be coupled to an electrode 36.

Electrode 36 can be made from any suitable electrically conductivematerial including, but not limited to, steel, copper, chromium, nickel,tungsten, iron, and similar materials. A first power source 38,electrically coupled to electrode 36 via electrical feedthrough port 40,can apply a voltage to electrode 36. In one example, power source 38 isan AC voltage source.

In one embodiment, an insulator 42, formed of a non-electricallyconductive material, including materials such as rubber, ceramic, orplastic is provided. Insulator 42 can include a connector 44, which canbe either electrically coupled to first power source 38 or anindependent second power source 48 for applying a voltage to a cage 50.In one example, a second power source 48 is a DC voltage source.

Cage 50 can be positioned within chamber 30 in symmetrical conformityabout medical device 34 so as to protect and reduce dielectric breakdownto medical device 34 due to arcing in the plasma field from alldirections. Cage 50 can be manufactured from a conductive material suchas carbon, or alternatively, can be made of a base material that iscoated with carbon. Alternatively, cage 50 can be made out of otherconductive materials such as metals, stainless steel, or titanium. Cage50 can be cylindrically shaped. Cage 50 can be perforated. By way ofexample, case 50 can be a perforated cylinder measuring approximately0.5 inches (1.27 cm) to 3.0 inches (7.62 cm) in diameter, approximately2 inches (5.08 cm) to 12 inches (30.48 cm) in height, and approximately{fraction (1/32)} of an inch (0.08 cm) thick. The diameter of theperforations can be from about 0.125 inches (0.318 cm) to about 0.25inches (0.635 cm). The percentage of the grid occupied by perforation,as opposed to conductive material, can be from about 40% to about 80% ofthe total surface area.

Gas ports 52 can be positioned on top of chamber 30, while aspirationports 54 can be positioned at or near the base of chamber 30. Gas ports52 are used to flux a gaseous medium in liquid or vapor form intochamber 30, where it is converted into ionized plasma. Aspiration ports54 are used after processing is complete, or when a new gas is desired,purge chamber 30.

Additionally, an apparatus for accomplishing the method of the presentinvention includes a plasma-generating assembly. The plasma-generatingassembly can be, for example, a radio frequency source and antenna, amicrowave source, or any other suitable element known to one of ordinaryskill in the art. By way of example, FIG. 10 illustrates a radiofrequency source 56, such as that manufactured by Dressler of Germany,and an antenna 58. In one such embodiment, antenna 58 can be aradio-frequency conducting filament that is wrapped about chamber 30 ina helical or corkscrew-like fashion.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modification can be made without departing from thisinvention it its broader aspects and, therefore the appended claims areto encompass within their scope all such changes and modifications asfall within the true spirit and scope of this invention.

It is illustrated that the present invention enables coating of the SODmonto the surface of a pacemaker lead. However, it should be appreciatedthat the methods and the SODm coating described above can be applied tomany other medical devices without deviating from the scope of thepresent invention. The method and the SODm coating described above areespecially useful for coating SODm onto hard to coat materials (e.g.,silicon rubber, fluoro polymer, polyethylene, and polypropylene) thatare used to make many medical devices.

1. A medical device comprising: a substrate having a plasma polymerizedfunctionality layer bonded to at least a portion of said substrate, saidplasma polymerized functionality layer comprising a first plurality offunctional groups; and a superoxide dismutase mimic agent having asecond plurality of functional groups complimentary to said firstplurality of functional groups.
 2. A medical device as in claim 1wherein said first plurality of functional groups is selected from thegroup consisting of carboxylate, amine, and sulfate.
 3. A medical deviceas in claim 1 wherein said first plurality of functional groupscomprises of amine functional groups.
 4. A medical device as in claim 1wherein said first plurality of functional groups comprises of acrylicacid functional groups.
 5. A medical device as in claim 1 wherein saidfirst plurality of functional groups comprises of amine functionalgroups, wherein said second plurality of functional groups alsocomprises of said second amine functional group, and wherein a pluralityof crosslinkers bonds said first plurality of functional groups saidsecond plurality of functional groups.
 6. A medical device as in claim 5wherein said plurality of crosslinkers comprises at least one ofhomobifunctional N-hydroxysuccinimide ester, disulfosuccinimidylsuberate, dissuccinimidyl suberate, bis(sulfosuccinimidyl)suberate, abis imidoester, dimethyl pimelimidate, dimethyl suberimidate, dimethyladipimidate, and dimethyl 3.3-dithiobispropionimidate.
 7. A medicaldevice as in claim 1 wherein said first plurality of functional groupscomprises of carboxylate functional groups, wherein said secondplurality of functional groups comprises of amine functional groups, andwherein said carboxylate functional groups bond to said amine functionalgroups.
 8. A medical device as in claim 1 wherein said first pluralityof functional groups comprises of acid chloride derivatives ofcarboxylate functional groups, said second plurality of functionalgroups comprises of amine functional groups, and said acid chloridederivatives bond to said amine functional groups.
 9. A medical device asin claim 1 further comprising a plurality of polyethylene glycolfunctional groups wherein said first plurality of functional groupscomprises of carboxylate functional groups, said second plurality offunctional groups comprises of amine functional groups, , and said aminefunctional groups and said plurality of polyethylene glycol functionalgroups bond to said carboxylate functional groups.
 10. A medical deviceas in claim 1 wherein said first plurality of functional groupscomprises of acid chloride derivatives of carboxylate functional groups,said superoxide dismutase mimic agent further having a plurality ofpolyethylene glycol functional groups, said second plurality offunctional groups comprises of amine functional groups, and wherein saidamine functional groups and said polyethylene glycol functional groupsbond to said acid chloride derivatives of carboxylate functional groups.11. A medical device as in claim 1 further comprises a polymericinsulation layer coated around said substrate wherein said plasmapolymerized functionality layer is bonded to at least a portion of saidpolymeric insulation layer.
 12. A medical device as in claim 1 whereinsaid substrate is formed at least in part of a polymeric materialselected from the group consisting of a fluoropolymer,polytetrafluoroethylene, expaned polytetrafluoroethylene, polyolefin,high density polyethylene, polyimide, polyetherether keytone, polyimide,polyether urethane, polyurethane, polycarbonate urethane, siliconizedurethane, and silicone rubber.
 13. A medical device as in claim 1wherein said polymerized functionality comprises a film having athickness of about 25 nm to about 250 nm.
 14. A medical device as inclaim 1 wherein said medical device is a pacemaker lead having acomponent formed at least in part of said substrate. 15-29. (Canceled).30. A medical device as in claim 1 further comprising an electricallyconductive electrophysiology lead implantable in a patient's hearthaving said substrate.
 31. A medical device as in claim 1 furthercomprising a pacemaker lead implantable in a patient's heart having saidsubstrate.
 32. A medical device as in claim 1 further comprising anelectrical signal generator and an electrically conductiveelectrophysiology lead implantable in a patient's heart having saidsubstrate.